The present invention relates to an apparatus and a method for localized delivery of therapeutic agents, and more particularly, to an implantable or insertable medical device having a coating, on at least a portion of a surface of the device, of a pH-sensitive polymer that allows release therefrom of a negatively charged therapeutic agent when contacted with a fluid at or above about a physiological pH.
The systemic administration of drug agents, such as by transdermal or intravenous means, treats the body as a whole even though the disease to be treated may be localized. In such a case, systemic administration may not be desirable because the drug agents often have unwanted effects on parts of the body that are not intended to be treated, or because treatment of the diseased part of the body requires a high concentration of drug agent that may not be achievable by systemic administration. For example, when administered to a patient systemically, some drugs (e.g., chemotherapeutic drugs such as those used to treat cancer and other proliferative disorders) may cause undesirable side effects.
It is therefore often desirable to administer drug agents at a localized site within the body. Localized drug delivery is often desirable for the treatment of heart disease by delivery of a therapeutic agent to an occluded or stenosed vascular lumen as well as to deliver therapeutic agents to other target sites in the body including other occluded or stenosed body lumens.
Various methods have been proposed for such localized drug administration. For example, U.S. Pat. No. 5,304,121, which is incorporated herein by reference, discloses a method of delivering water-soluble drugs to tissue at a desired location of a body lumen wall. The method includes the steps of impregnating a hydrogel polymer provided as a coating on a balloon catheter or other implantable or insertable medical device with an aqueous drug solution, inserting the catheter into a blood vessel at a desired location, and expanding the balloon portion of the catheter against the surrounding tissue to allow the release of the drug from the hydrogel polymer coating. The drug is preferably released from the hydrogel polymer coating upon compression thereof against the body lumen wall. This method of drug delivery is convenient, but is limited by the fact that many drugs either release from the hydrogel before reaching the target site or are not released effectively when the target site is reached.
There remains a need for effective localized delivery of therapeutic agents. In particular, there exists a need for localized delivery of negatively charged therapeutic agents such as nucleic acid, for example. Nucleic acids are often difficult to remove when immobilized in a conventional polymer coating containing fixed positively charged moieties, i.e., moieties whose charge does not substantially depend on the ambient pH conditions. Thus, there is a need for a method for obtaining the release of therapeutic agents from a medical device at a target site within the body, particularly for the release of therapeutic agents from a medical device provided with a coating on at least a portion of a surface thereof which coating also contains therein or thereon a therapeutic agent, preferably a negatively charged therapeutic agent.
In one aspect, the present invention is directed to an implantable or insertable therapeutic agent delivery device comprising a coating material provided on at least a portion of a surface of the device, the coating material prohibiting substantial release therefrom of a therapeutic agent at or below about a physiological pH and allowing substantial release therefrom of a therapeutic agent at or above about physiological pH. In a preferred embodiment of the present invention, the coating material further comprises the therapeutic agent. Preferably, the therapeutic agent is negatively charged and the coating material comprises moieties that carry a positive charge at a pH at or below about physiological pH and are substantially uncharged at or above about physiological pH. Thus, the coating materials of the present invention are provided with moieties whose charge depends on pH, rather than being substantially fixed, i.e., substantially unaffected by varying pH conditions, such as occurs by known methods of derivatization of coating materials. Preferably, the moieties have a pKa less than about physiological pH. In a preferred embodiment, the polymeric material comprises a polymer which is preferably a poly(acrylic acid) polymer. In a particularly preferred embodiment, the poly(acrylic acid) polymer is a hydrogel polymer. In another preferred embodiment, moieties whose charge depends on pH as described herein are provided by compounds selected from the group consisting of aminoethyl pyridine or aminopropyl imidazole, each of which contains a moiety having a pKa less than about 7.4. In a preferred embodiment, the polymer is derivatized with at least one of these preferred compounds to result in a derivatized polymer containing moieties whose charge depends on pH as disclosed herein.
In another aspect, the present invention is directed to a method for delivering a therapeutic agent to a mammal by implanting or inserting into a mammal an implantable or insertable medical device according to the present invention.
In another aspect, the present invention is directed to a method of derivatizing a polymer by reacting, in the presence of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride or dicyclohexylcarbodiimide, carboxyl groups in the polymer with a compound containing a moiety that has a positive charge at or below about physiological pH and that is substantially uncharged at or above about physiological pH. Preferably, the moiety in the compound reacted with the polymer has a pKa less than physiological pH of about than 7.4. The preferred compounds containing a moiety that has a pKa less than a physiological pH of about 7.4 are basic compounds of which aminoethyl pyridine and aminopropyl imidazole are most preferred.
In yet another aspect, the present invention is directed to a polymer made by the method described above.
In another aspect, the present invention is directed to a method of coating at least a portion of the surface of an implantable or insertable medical device comprising contacting the medical device with a coating material that prohibits substantial release therefrom of a therapeutic agent at or below about physiological pH and allows substantial release therefrom of a therapeutic agent at or above about physiological pH. In preferred embodiments, the medical device is contacted with the coating material by dipping the implantable or insertable medical device into a solution or suspension of the coating material, or by spraying a solution or suspension of the coating material onto at least a portion of the implantable or insertable medical device.
In yet another aspect, the present invention is directed to a method of coating at least a portion of an implantable or insertable medical device comprising contacting the medical device with a polymer and subsequently reacting, in the presence of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride or dicyclohexylcarbodiimide, carboxyl groups in the polymer with a compound that contains a moiety that is positively charged at or below about physiological pH and that is substantially uncharged at or above about physiological pH, thereby forming a coating on at least a portion of the implantable or insertable medical device which prohibits substantial release therefrom of a therapeutic agent at or below about physiological pH and which allows substantial release therefrom of a therapeutic agent at or above about physiological pH.